tbuckley/cabot-search huggingface dataset:
Phase 1 study of LP-108 as monotherapy and in combination with azacitidine in patients with relapsed or refractory myelodysplastic syndromes (MDS), chronic myelomonocytic leukemia (CMML), or acute myeloid leukemia (AML).
Authors: Alison R. Walker, Juan Miguel Bergua Burgues, Pau Montesinos, Dale Bixby, Naval Guastad Daver, Marina Konopleva, Stephen Patrick Anthony, Fenlai Tan, Yi Chen, Yu Chen, Yue Shen, Patrick William Burke
Journal: Journal of Clinical Oncology (2022)

TPS7071 Background: BCL2 inhibition as a means of targeting intrinsic apoptotic pathways that confer a survival advantage to leukemic blasts has become a key therapeutic strategy for patients with myeloid malignancies. LP-108 is an oral highly potent and selective inhibitor of BCL-2 with comparable or more potent in vitro inhibitory activity as compared to the FDA approved oral BCL-2 inhibitor venetoclax. We propose to investigate LP-108 as monotherapy and in combination with azacitidine in patients with relapsed or refractory (r/r) MDS, CMML or AML. Methods: The primary objectives of the trial are 1.) To determine the safety, tolerability and determine the maximum tolerated dose (MTD) and the recommended phase 2 dose / optimal biological dose (OBD) of LP-108 as a single agent (Arm 1) and in combination with azacitidine (Arm 2) in patients with relapsed/refractory MDS/CMML/AML; 2.) To characterize the pharmacokinetic profile of LP-108 as monotherapy and in combination with a fixed dose of azacitidine. The secondary objectives of the trial are 1.) To evaluate the objective response rate of LP-108 (monotherapy or combination therapy) in r/r MDS/CMML/AML as well as progression free survival, duration of response and overall survival. In Arm 1 patients will be enrolled according to a 3+3 design with escalating doses of LP-108 for a 28 day cycle (firs table). DLTs will be determined in the first 28 days. In Arm 2 patients will be enrolled according to a 3+3 design with escalating doses of LP-108 in combination with a fixed dose of azacitidine (second table). DLTs will be determined in the first 28 days. DLT for both arms is defined as some ≥ Grade 3 non-hematological toxicities or prolonged myelosuppression. Patients may continue treatment until disease progression, unacceptable toxicity, or per investigator discretion. Patients age ≥ 18 years with r/r MDS with excess or blasts or with high or very-high risk disease per the R-IPSS, or r/r MDS for Arm 2, r/r AML, or frontline older and/or unfit AML for Arm 2, or r/r CMML may enroll. Patients with prior hypomethylating agents or venetoclax exposure may enroll. The blast count at the time of starting therapy must be ≤ 30 x 10 9 cells/L. Hydroxyurea is allowed prior to and during treatment. Ejection fraction ≥ 50% is required. Calculated creatinine clearance shall be ≥ 30 mL/min. Strong CYP3A4 inducers and inhibitors are prohibited. Patients on weak/moderate azole antifungals were allowed to enroll. Enrollment to Arm 1 is complete and there have been no DLTs to date. Enrollment to Arm 2 is pending. Arm 1 Dose Escalation Scheme (LP-108 monotherapy). Clinical trial information: NCT04139434. [Table: see text][Table: see text]
A RAS-independent biomarker panel pedicts response to MEK-inhibitors in colorectal cancer.
Authors: Ulrike Pfohl, Jürgen Loskutov, Sanum Bashir, Ralf Kühn, Markus Templin, Soulafa Mamlouk, Sergei Belanov, Marcus Vetter, Christoph Reinhard, Lena Wedeken, Christian RA Regenbrecht
Journal: Journal of Clinical Oncology (2022)

e15524 Background: Biomarker discovery and development are essential for stratifying cancer patients in order to improve treatment outcomes. In colorectal cancer (CRC), mutations in the TGF-β/BMP pathway, especially in the SMAD4 gene have been correlated with decreased overall survival and are suspected to modulate drug sensitivity on the cellular level, hence SMAD4 mutations are worthwile targets for novel targeted therapy aproaches. Methods: In the present study, we uncover the mechanistic role of a loss-of-function mutation in SMAD4 in syngeneic patient-derived organoids (PDOs). CRISPR-engineered SMAD4 R361H PDOs were subjected to a comparative drug screening, RNA-Sequencing and multiplex protein profiling analysis (DigiWest®). We have confirmed the response towards MEK inhibition of the initial model in an additional set of 62 PDOs with known mutational status. Results: We show that acquisition of SMAD4 loss-of-function mutations renders PDOs sensitive to MEK-inhibitors. Further, an activation of the TGF-β/BMP signaling pathway, specifically of the BMP branch was observed in SMAD4 wt PDOs; indicating that BMP signaling is likely responsible for the resistance towards MEK inhibition. It is plausible that functional loss of SMAD4 and thus loss of BMP signaling renders SMAD4 mutated tumors more sensitive to MEK-inhibitors. By looking at additional genes involved in TGF-β/BMP signaling that are frequently mutated in CRC, we identified the novel gene mutational SFAB-signature ( SMAD4, FBXW7, ARID1A, or BMPR2), when at least one pathogenic mutation is present in these genes. The frequency of SFAB in CRC patient cohort (TCGA, n = 594) was comparable to the frequency of SFAB in our PDOs. For PDOs with SFAB-signature, we found up to 95% and 70% significant positive prediction for cobimetinib and selumetinib, respectively and also up to 70% positive prediction for trametinib. Thus, the SFAB-signature predicts response to MEK inhibition in PDOs with a very high confidence. We further investigated whether the RAS status of CRC PDOs does predict sensitivity to MEK inhibition. The RAS status alone and in combination with SFAB-signature failed to yield better prediction sensitivity to MEK-inhibitors. Conclusions: The present study is a significant step forward to more personalized treatment regimens for CRC patients by early inclusion of MEK-inhibitors. The SFAB-signature should be put to clinical testing as a RAS-independent biomarker for stratification of patients providing a valuable alternative treatment option against CRC, thus ensuring that all patients receive effective and specific therapies as early as possible.
Long-term outcomes of newly diagnosed CRLF2 rearranged B-cell ALL.
Authors: Jayastu Senapati, Elias Jabbour, Nicholas James Short, Farhad Ravandi, Partow Kebriaei, Tapan M. Kadia, Gautam Borthakur, Naveen Pemmaraju, Rebecca Garris, Divyam Bansal, Sergej Konoplev, Sa A Wang, Wei Wang, Guilin Tang, Keyur P. Patel, Marina Konopleva, Nitin Jain
Journal: Journal of Clinical Oncology (2022)

7040 Background: CRLF2 rearranged B-ALL, a subtype of Ph-like ALL, constitutes a high-risk subset of B-ALL with poor outcomes with chemotherapy. Targeted therapies such as blinatumomab (blina) or inotuzumab (ino) may improve treatment outcomes for these patients (pts). Methods: We retrospectively analyzed pts with newly diagnosed B-ALL (diagnosed between 01/2001 and 12/2021) at our center who had documented CRLF2 overexpression. Initial therapy, including use of ino and blina in CR1 were noted. Outcomes measures included CR/CRi, MRD response, RFS and OS. Results: A total of 76 pts with a median age of 38 years (yrs) (range, 18-80) were identified, of which 70% were males and 81% were of Hispanic ethnicity. All pts had overexpression of CRLF2 documented by flow cytometry or gene expression profile. A subset of pts (n=37) had a concomitant CRLF2 FISH performed with all confirming CRLF2 rearrangement. Baseline disease parameters, treatment and outcomes are detailed in Table. Sixty-five pts (85%) received Hyper-CVAD based induction therapy (HCVAD, n=51; mini-HCVD, n=14) and 11 (15%) received augmented BFM. Among the HCVAD/mini-HCVD treated pts, 37% received blina in CR1 during consolidation at a median of 3.6 months after starting induction therapy, 34% received ino in CR1 (most commonly starting in cycle 1 as part of mini-HCVD + ino regimen) and 22% received both ino and blina in CR1. We focus on the outcomes of 65 pts treated with HCVAD/mini-HCVD. The median follow-up was 18 months (mos). CR/CRi rate after C1 among HCVAD/mini-HCVD treated pts was 52/65 (80%) with 25/47 (53%) MRD evaluable pts achieving MRD-neg post C1. The median RFS and OS was 17.6 and 26.6 mos, respectively. CR/CRp rate after C1 among pts who received mini-HCVD + ino in C1 was 100% (14/14) with 79% MRD-neg. On landmark analysis to the time to blina initiation, blina treated pts had similar RFS and trended for improved OS. A total of 19/65 (30%) had allo-SCT in CR1; all were MRD-neg prior to allo-SCT. Landmark analysis for OS based on time to allo-SCT (6 mos) favored SCT in CR1 (47.2 vs. 17.6 mos, p=0.04). Conclusions: Despite improvements in treatment options, CRLF2 overexpressed B-ALL continue to have inferior outcomes. Earlier initiation of targeted therapies might improve outcomes.[Table: see text]
The impact of the multidisciplinary team (MDT) in the management of colorectal cancer (CRC).
Authors: Annunziato Anghelone, Maria Bensi, Brunella Barbaro, Maria Alessandra Calegari, Caterina Cina, Roberta Menghi, Laura Lorenzon, Carmelo Pozzo, Michele Basso, Francesco Schietroma, Giustina Valente, Filippo Lococo, Francesco Ardito, Francesco Cellini, Giulia Caira, Giovanni Trovato, Domenico D'Ugo, Felice Giuliante, Giampaolo Tortora, Lisa Salvatore
Journal: Journal of Clinical Oncology (2022)

e13641 Background: The management of CRC is complex, particularly in metastatic disease, where it is crucial the definition of disease burden, the assessment of radiological response and the identification of the right timing for potential radical surgery or loco-regional treatments. A correct CRC evaluation and the subsequent choice of the most appropriate treatment strategy, need, therefore, a MDT involving surgeons, oncologists, radiologists, radiation oncologists, endoscopists, gastroenterologists and pathologists. Based on such considerations, we investigated the impact of the MDT meeting in the management of CRC at our Institution. Methods: We retrospectively evaluated all the cases discussed at our MDT meeting between September 2019 and September 2021. We collected data, both pre- and post-MDT meeting, regarding radiology evaluation (disease control vs progression), surgical assessment (yes vs no) and radiotherapy evaluation (yes vs no). Primary endpoint was the overall rate of discrepancy in evaluation between pre- and post-MDT meeting. Results: Between September 2019 and September 2021, 696 cases were presented at our MDT meeting. The median age was 65 years (24-86), 391 (56%) patients were male and 553 (79%) patients had metastatic disease at diagnosis. After MDT meeting, a total of 214 decisions were modified, for an overall discrepancy rate of 31%. In particular, among 377 cases discussed for radiology evaluation, 110 decisions (29%) were modified after a central imaging review: 80 cases initially evaluated as progressed disease before MDT meeting were defined stable after MDT meeting, for a discrepancy rate of 73%. Regarding the 246 cases discussed for surgical assessment on primary tumor and/or metastatic sites, treatment strategy changed in 86 cases (35%). More specifically, 16 cases (19%), evaluated unresectable before MDT meeting, were then considered resectable after MDT meeting. Finally, among the 71 cases discussed for radiotherapy evaluation, treatment strategy changed in 18 cases (25%). Conclusions: Our analysis demonstrates a significant rate of discrepancy in radiology and/or surgical evaluation between pre- and post-MDT meeting. Our results show that a MDT allows a considerable modification in CRC management, maximizing the treatment strategy, in particular avoiding unnecessary changes in therapy and allowing surgery where possible.
Neuropathy and neurocognitive impairment in long-term survivors of pediatric cancer treated without central nervous system (CNS) directed therapy.
Authors: AnnaLynn Williams, Nicholas Steve Phillips, Chelsea Goodliffe Goodenough, Tara M. Brinkman, Chiara Papini, Lisa M Jacola, Angela M. Delaney, Gregory T. Armstrong, John L. Jefferies, Raja B. Khan, Leslie L. Robison, Melissa M. Hudson, Kirsten K. Ness, Kevin R. Krull
Journal: Journal of Clinical Oncology (2022)

10020 Background: Survivors of pediatric cancer, including those without CNS-directed treatment, are at risk of neurocognitive impairment and peripheral or autonomic neuropathies; conditions that co-occur in non-cancer populations. Using the St. Jude Lifetime Cohort, we investigated associations between these sequelae to inform contributors to long-term cancer-related neurocognitive impairment. Methods: Clinically assessed survivors of pediatric cancer (N=2,138, mean age 31 [SD 13], 23[11] years from diagnosis, 51% male) not treated with CNS-directed therapy completed neurocognitive testing. Modified total neuropathy score peripheral sensory and motor subscales were combined with functional tasks and severity graded using a modified NCI CTCAE. Cardiac autonomic neuropathy was defined as impaired heart rate reserve (&lt;80% age- sex-predicted or ≤62% with beta blocker). Separate log binomial regression models estimated risk of neurocognitive impairment (age adjusted z-score &lt;10 th percentile) associated with grade 2+ sensory, motor or autonomic neuropathy. Path analysis examined if pain with daily interference mediated associations between motor or sensory neuropathy and neurocognitive impairment. Results: 838 (39%) survivors had autonomic, 115 (5.4%) had motor and 162 (7.6%) had sensory neuropathy. Compared to those with no neuropathy, survivors with motor or sensory neuropathy had a higher risk of impairment in sustained attention, visual-motor processing speed, short- and long-term memory, and executive function (Table, p’s&lt;0.01). Autonomic neuropathy was associated with a higher risk of impairment in visuo-motor processing speed (p=0.03). Pain partially mediated associations between sensory neuropathy and sustained attention (10% mediated, p=0.04), visual-motor processing speed (8% p=0.02), and executive function (14% p=0.02). Pain was not related to motor neuropathy. Conclusions: Peripheral and autonomic neuropathies are associated with significant risk of neurocognitive impairment in adult survivors of pediatric cancer. Research is needed to further understand shared mechanisms (e.g., pain, inflammation) to design targeted interventions to improve neuropathic symptoms and neurocognitive function. [Table: see text]
ATTAC-MCC: Phase I/II study of autologous CD8+ and CD4+ transgenic T cells expressing a high affinity MCPyV-specific TCR combined with checkpoint inhibitors and class I MHC-upregulation in patients with metastatic MCC refractory to PD-1 axis blockade.
Authors: Joshua Veatch, Ananth Akkiraju, Agus Darwanto, Sean Garrity, Damien Hallet, Kim Nguyen, Piotr Pierog, Tomasz Sewastianik, Markus P Vallaster, Loic Vincent, Aude Chapuis
Journal: Journal of Clinical Oncology (2022)

TPS9596 Background: Merkel cell carcinoma (MCC) is a highly aggressive skin cancer, with an incidence that has doubled in the last 20 years to approximately 3000 cases/year in the US. Over one-third of patients will develop widespread disease, and survival in these patients has been historically poor with a 5-year survival rate of &lt; 10%. MCC is highly immune-sensitive due to the antigenicity of the cancer-causing Merkel cell polyomavirus (MCPyV) expressed in most MCC tumors. Although immune checkpoint inhibitors (ICIs) targeting the PD-(L)1 axis show promising efficacy, most MCC patients will eventually relapse. There is no standard of care for patients that become refractory to ICIs. We hypothesize that cellular immune therapies targeting MCPyV may provide additional clinical benefit to these patients. To test this, we have engineered high-affinity TCR T cells against MCPyV and initiated a clinical trial. Methods: NCT03747484 is an ongoing phase I/II, open label, investigator-initiated trial (IIT) of FH-MCVA2TCR in combination with an anti-PD-(L)1 checkpoint inhibitor and an agent to upregulate MHC-I expression on tumor cells. The trial is conducted in patients aged 18 years or older with metastatic or unresectable, histologically confirmed virus-positive MCC whose disease has progressed on or after treatment with a PD-(L)1 axis checkpoint inhibitor. Patients undergo leukapheresis to collect white blood cells (WBCs) for TCR T cell product manufacturing. The cell product is administered on day 0. Patients receive an agent to upregulate MHC-I on tumor cells and continue on an anti-PD-(L)1 checkpoint inhibitor for up to one year. In phase I, three patients receive up to two infusions of dose level 1 of the T cell product. The primary objectives of phase I are to determine safety and tolerability based on dose-limiting toxicities (DLT) during an observation period of 28 days after the first infusion. Phase II enrolls patients at dose level 2. The total sample size of phase II is 12 patients. The first three patients are enrolled in a staggered manner and observed for DLTs. If no DLTs occur, the remaining sample size is accrued in open enrollment. The main objectives of phase II are safety based on number of adverse events and preliminary efficacy based on tumor response according to RECISTv1.1 and iRECIST. Secondary/exploratory objectives include cellular kinetics of TCR T cells, T cell phenotype, tumor infiltration kinetics, and MHC-I expression dynamics over time. After the first 12 months, patients transition to a long-term follow-up (LTFU) study for up to 15 years as per FDA guidelines. Clinical trial information: NCT03747484.
Preventing adverse events in patients with renal cell carcinoma treated with doublet immunotherapy using fecal microbiota transplantation (FMT): Initial results from perform a phase I study.
Authors: Ricardo Fernandes, Seema Nair Parvathy, D. Scott Ernst, Mansour Haeryfar, Jeremy Burton, Michael Silverman, Saman Maleki
Journal: Journal of Clinical Oncology (2022)

4553 Background: The treatment landscape of metastatic renal cell carcinoma (mRCC) has evolved with the advent of either dual immune checkpoint inhibition (ICI) or in combination with Vascular Endothelial Growth Factor Receptor Tyrosine Kinase Inhibitor. Gut microbiota plays a central role in developing local and systemic immunity, with potential influence in controlling anti-tumor immune response in cancer patients treated with ICI. We hypothesize that FMT from healthy donors given before immunotherapy will establish a more resilient gut microbiota, reducing the treatment toxicity and improving response to therapy. PERFORM is an ongoing phase I study evaluating the safety of FMT and immunotherapy combination in first-line (1L) mRCC, and assessing whether FMT will prevent or mitigate immune-related adverse events (irAE). Methods: Eligible patients with untreated mRCC received a full dose and 2 supportive FMT procedures prior to the first 3 cycles of doublet ICI or in combination with VEGF-TKI. Primary endpoint is the feasibility and safety of combining FMT using intestinal bacteria existing in the stool of healthy donors with immunotherapy. Secondary endpoints include incidence of irAEs, objective response rate (ORR; RECIST v1.1), and changes in pts microbiome and immune profile post-FMT. We included a preliminary analysis of the first 10 patients. Results: 10 patients received FMT and doublet ICI therapy (10 ongoing). 8/10 (80%) patients were male. Median Age: 59.5 (53-71) years-old. Most common histology was clear cell RCC (90%) and all patients had an intermediate or poor-risk disease. 93.3% of planned FMT were administered. No dose-limiting toxicities due to FMT were observed. Median (range) follow-up was 5.5 (1–22) months. 4 patients (40%) discontinued treatment due to irAEs: colitis (n = 3), arthritis (n = 1). IrAEs were reported in 8 (80%) patients, including diarrhea (n = 6; 60%) and skin rash (n = 2, 20%). Grade 3/4 AEs were experienced by 6 (60%) patients, including colitis (n = 4, 40%). ORR was confirmed in 4/9 patients (44%; 95% CI, 30–60); 1 (11%) partial response. Microbiota and immune analysis data to be presented. Conclusions: The role of microbiome modification in preventing immune-related toxicities by adding FMT to ICI therapy was associated with a safety profile in unselected 1L mRCC and promising clinical efficacy data. Further prospective studies to examine the changes in the immune and microbiota profiles to determine biomarkers related to healthy outcomes/less frequent toxicities in patients receiving immunotherapy are warranted. Clinical trial information: NCT04163289.
Phase 1 study of SGN-ALPV, a novel, investigational vedotin antibody–drug conjugate directed to ALPP/ALPPL2 in advanced solid tumors (SGNALPV-001, trial in progress).
Authors: Nehal J. Lakhani, Claire Frances Friedman, Cesar Augusto Perez, Alison Wehr, Suzanne M. McGoldrick, Patricia LoRusso
Journal: Journal of Clinical Oncology (2022)

TPS3159 Background: Alkaline phosphatase placental (ALPP) and ALPP-like 2 (ALPPL2) are proteins with 98% sequence similarity that are highly expressed in ovarian, endometrial, gastric, and testicular cancers. Restricted normal tissue expression and efficient lysosomal trafficking of ALPP and ALPPL2 highlight their potential as anticancer targets. SGN-ALPV is a novel investigational vedotin antibody–drug conjugate composed of a humanized anti-ALPP/ALPPL2 monoclonal antibody, a protease-cleavable linker, and the microtubule disrupting agent monomethyl auristatin E (MMAE). The proposed mechanism of action of SGN-ALPV is binding to ALPP/ALPPL2 on the cell surface, where it is internalized and trafficked to the lysosome. Lysosomal proteases cleave the linker to release MMAE into the cytoplasm, where it binds and disrupts the microtubule network, causing cell cycle arrest and apoptosis. Additional mechanisms of action of SGN-ALPV include immunogenic cell death and apoptosis of neighboring cells via the bystander effect. Promising preclinical data support the evaluation of SGN-ALPV in a clinical trial. Methods: SGNALPV-001 (NCT05229900) is a phase 1, open-label, multicenter study designed to evaluate the safety, tolerability, pharmacokinetics (PK), and antitumor activity of SGN-ALPV in patients (pts) with select advanced solid tumors. This study consists of 3 parts: dose escalation (Part A), dose and schedule optimization (Part B), and dose-expansion in disease-specific cohorts and a biology cohort (Part C). Adult pts (≥18 years) with confirmed ovarian, endometrial, non-small cell lung, gastric, cervical cancer, or testicular germ-cell tumors, relapsed or refractory to approved therapies, with measurable disease per RECIST v1.1 and an ECOG PS 0–1 are eligible. Primary endpoints include incidence of adverse events, laboratory abnormalities, dose-limiting toxicities, and cumulative safety. Secondary endpoints include estimates of antidrug antibodies, PK parameters, objective response rate, duration of response, progression-free survival, and overall survival. Exploratory endpoints are pharmacodynamic and biomarker measurements. Safety and antitumor activity endpoints will be summarized using descriptive statistics. Enrollment for Part A is ongoing in sites in North America and Europe. Enrollment for Parts B and C will be opened upon completion of Part A. Clinical trial information: NCT05229900.